Viruses, unlike bacteria, rely on the host cell for their replication. The first step of a virus's lifecycle is attachment to the host cell. This attachment to initiate replication often relies on the interaction of viral proteins attaching to poly saccharides found in the extracellular matrix (ECM) surrounding the cells. One of the linear polysaccharides in the ECM that viruses use is heparan sulfate (HS). A variety of different virus families use heparan sulfate for entry including members of the Herpesviridae, Paramyxoviridae, Picornaviridae, Parvoviridae, Retroviridae, and Poxviridae. Although the exact mechanism of attachment is unknown, it is assumed that blocking entry into the host cell will prevent virus infection and limit viral spread within the host.
Heparan sulfate (HS) when present on a cell surface, provides an attachment site for many human and non-human pathogenic viruses including herpes simplex virus type-1 and -2 (HSV-1 and HSV-2, respectively). HSV binds to heparan sulfate and HSV-1 penetration into cells can also be mediated by 3-OS heparan sulfate, which is produced after a rare enzymatic modification in HS catalyzed by 3-O-sulfortransferases (3-OSTs). HSV envelope glycoproteins B and C (gB and gC) bind HS and mediate virus attachment to cells. A third glycoprotein, gD, specifically recognizes 3-OS HS in a binding interaction that facilitates fusion pore formation during viral entry.
The versatility of HS to bind multiple microbes and participate in a variety of regulatory phenomena comes from its negatively-charged nature and highly complex structure, which is generated by enzymatic modifications. Virtually all cells express HS as long un-branched chains often associated with protein cores commonly exemplified by syndecan, perlecan and glypican families of HS proteoglycans. The parent HS chain, which contains repeating glucosamine and hexuronic acid dimers, can be 100-150 residues long and may contain multiple structural modifications. Most common among them is the addition of sulfate groups at various positions within the chain, which leads to the generation of specific “heparin-like” highly electronegatively charged motifs making HS very attractive for viral and microbial adherence.
Emerging evidence suggests that the role of HS in viral infection extends beyond its function as a low-specificity pre-attachment site. For instance, HS mediates HSV-1 transport on filopodia during surfing (and negatively regulates virus-induced membrane fusion). Likewise, for human papilloma virus (HPV), HS proteoglycans play a key role in the activation of immune response, an important aspect for both vaccine development and HPV pathogenesis. Similarly, HS expressed on spermatozoa plays a key role in the capture of human immunodeficiency virus (HIV) and its transmission to dendritic, macrophage, and T-cells. Further, the first step during cytomegalovirus CMV infection is attachment via HS, and then subsequent steps follow. Heparan sulfate also plays a role in hepatitis B virus replication.
Despite the promise shown by HS in the development of a viral therapy, what remains critically needed are anti-HS inhibitors that prevent the cellular infection by viruses, including HSV and CMV. For example, therapeutics that target HS—and thus a critical step in HSV and CMV infection of the host cell—would be valuable, inasmuch as current therapeutics for these and other viral infections include antiviral drugs. But problems with the current anti-viral drugs include increased viral resistance and harmful side effects, like nephrotoxicity. New therapeutics are thus needed that are both less toxic and are less likely to trigger resistance in infections such as HSV and CMV infections.